This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Calcium ions are potent intracellular messengers. They can enter the cytoplasm from the extracellular space or from intracellular stores such as the endoplasmic reticulum. Upon entry into the cytoplasm, they mediate important events such as regulation of our heartbeats, the contraction of skeletal and cardiac muscle, and the release of hormones and neurotransmitter. In this project, we focus on two very large classes of membrane proteins that allow calcium entry: voltage-gated calcium channels and ryanodine receptors. Mutations in either channel class underlie many genetic diseases that are often fatal, and they form targets for drugs to treat cardiovascular diseases, chronic pain, and epilepsy. We aim to understand how these channels work in physiological and diseased states, by obtaining crystal structures of novel channel domains and their disease mutants, both alone and in complex with regulatory proteins. Crystals for both wild type and mutant domains are already present. We require synchrotron radiation to allow a sufficiently high resolution and to use MAD for solving the structures.